Toglia Patrick, Cheung King-Ho, Mak Don-On Daniel, Ullah Ghanim
Department of Physics, University of South Florida, Tampa, FL 33620, United States.
School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Cell Calcium. 2016 May;59(5):240-50. doi: 10.1016/j.ceca.2016.02.013. Epub 2016 Mar 5.
Mutants in presenilins (PS1 or PS2) is the major cause of familial Alzheimer's disease (FAD). FAD causing PS mutants affect intracellular Ca(2+) homeostasis by enhancing the gating of inositol trisphosphate (IP3) receptor (IP3R) Ca(2+) release channel on the endoplasmic reticulum, leading to exaggerated Ca(2+) release into the cytoplasm. Using experimental IP3R-mediated Ca(2+) release data, in conjunction with a computational model of cell bioenergetics, we explore how the differences in mitochondrial Ca(2+) uptake in control cells and cells expressing FAD-causing PS mutants affect key variables such as ATP, reactive oxygen species (ROS), NADH, and mitochondrial Ca(2+). We find that as a result of exaggerated cytosolic Ca(2+) in FAD-causing mutant PS-expressing cells, the rate of oxygen consumption increases dramatically and overcomes the Ca(2+) dependent enzymes that stimulate NADH production. This leads to decreased rates in proton pumping due to diminished membrane potential along with less ATP and enhanced ROS production. These results show that through Ca(2+) signaling disruption, mutant PS leads to mitochondrial dysfunction and potentially to cell death.
早老素（PS1或PS2）突变是家族性阿尔茨海默病（FAD）的主要病因。导致FAD的PS突变体通过增强内质网上肌醇三磷酸（IP3）受体（IP3R）钙释放通道的门控来影响细胞内钙（Ca2+）稳态，从而导致过多的Ca2+释放到细胞质中。利用实验性IP3R介导的Ca2+释放数据，结合细胞生物能量学的计算模型，我们探讨了对照细胞和表达导致FAD的PS突变体的细胞中线粒体Ca2+摄取的差异如何影响关键变量，如ATP、活性氧（ROS）、NADH和线粒体Ca2+。我们发现，由于表达导致FAD的突变体PS的细胞中胞质Ca2+过多，耗氧率急剧增加，并超过了刺激NADH产生的Ca2+依赖性酶。这导致质子泵浦速率降低，原因是膜电位降低，同时ATP减少，ROS产生增加。这些结果表明，通过Ca2+信号传导破坏，突变体PS导致线粒体功能障碍并可能导致细胞死亡。
